Method for producing micrometer-sized polymer capsules

Abstract

The present invention relates to a method for producing polymeric microcapsules, comprising the steps of: a. preparation of an emulsion comprising an aqueous continuous phase and a dispersed phase in the form of microdroplets using microfluidic technology, wherein the dispersed phase comprises a monomer or prepolymer A and a cosolvent that is at least partially miscible in the continuous phase; b. Allowing the co-solvent of the dispersed phase to partially or completely diffuse into the continuous phase by diffusion and / or convection; c. Contacting the emulsion microdroplets with a polymerization solution containing a second monomer or prepolymer B to perform interfacial polymerization.

Description

[Technical Field]

[0001] The present invention relates to the field of methods for producing microcapsules and to the uses of said microcapsules. [Background technology]

[0002] Polymeric microcapsules, i.e., capsules with micrometer-sized dimensions and a polymer shell and a solid or liquid core, are found in many applications and diverse fields, such as cosmetics, pharmaceuticals, pesticides, paints and coatings.

[0003] For example, in the medical field, encapsulation of active ingredients that are rapidly metabolized by degradative enzymes or degraded by the acidic pH of the stomach allows for the protection, transport, targeting, and administration of these substances locally to selected tissues and organs in a controlled manner.

[0004] A common method for producing polymeric microcapsules involves preparing an emulsion followed by interfacial polymerization (IFP) to form a polymeric shell around droplets of the dispersed phase.

[0005] In this method, the emulsion is prepared in advance by mixing the dispersed phase solution and the continuous phase solution in a reactor to form an emulsion.

[0006] The dispersed phase solution contains a first monomer A.

[0007] An interfacial polymerization step is carried out after contacting the dispersed phase droplets with a polymerization solution containing a second monomer B. Polymerization by polycondensation of monomer A with monomer B at the interface of the two phases allows the formation of the microcapsule shell in situ.

[0008] The shell obtained by interfacial polycondensation is a polyamide, polyurethane, polyurea, polyester, or polycyanoacrylate obtained by polymerization of the monomers or prepolymers A and B shown in Table 1.

[0009] [Table 1]

[0010] These standard mixing techniques under high shear conditions in batch processes provide poor control over the size distribution of the droplets and, consequently, the size distribution of the capsules formed.

[0011] Because droplet size directly affects microcapsule properties such as the release profile of the active ingredient, permeability, and stability over time, processes have been proposed to produce smaller, more uniform microcapsules, with particular focus on means to reduce or control droplet size.

[0012] In particular, the use of microfluidic devices allows the production of monodisperse microcapsules, and this type of device has been extensively described in the literature.

[0013] Chinese Patent Application Publication No. 111437895 relates to a method for producing nanocapsules and microcapsules and a microfluidic device.

[0014] Polenz et al. (Ingmar Polenz, David A. Weitz and Jean-Christophe Baret, Langmuir 2015, 31, 3, 1127-1134) describe a method for producing monodisperse polyurea microcapsules using microfluidic devices and interfacial polymerization. Their results show that the properties of the polymer shell depend significantly on the type of surfactant present and the energy applied to the droplet-forming system.

[0015] WO 2007 / 150030 discloses a microfluidic system for use in the production of nanoparticles for use as drug carriers.

[0016] Thorne et al. (Thorne, M.F., Simkovic, F. & Slater, A.G. Production of monodisperse polyurea microcapsules using microfluidics. Sci Rep 9, 17983, 2019) discloses the use of a microfluidic device to produce polyurea microcapsules with a limonene core having average diameters of 27, 30, 32, 34, and 35 μm and a low dispersity of approximately ±2 μm.

[0017] Jiupeng Du's paper, "Preparation of polyurea microcapsules calibrated in size and shell thickness by a microfluidic process for the absorption of ultraviolet light," published on March 13, 2022, describes the development of polymer capsules with tuned size and shell thickness using a microfluidic device. This is applicable to the cosmetics industry through the encapsulation of sunscreen.

[0018] However, these microfluidic emulsification methods have a major drawback in that the minimum diameter of the microdroplets formed is limited by the size of the channels and flow rates used, and it is not possible to form microcapsules larger than a certain size set by the equipment used.

[0019] Therefore, although the use of microchannels with small cross sections could be a solution to producing microcapsules with smaller diameters, in practice it is not an effective solution because it requires a significant reduction in the flow rate in the microchannel, limiting productivity. Furthermore, the microchannels may become clogged, making them difficult to use.

[0020] Thus, there is still an unmet need for improved methods for producing microcapsules or microparticles with uniform size and shape, i.e., low polydispersity (coefficient of variation less than 15%, or even less than 7%), whose shell thickness is controlled, constant and uniform, and which have micrometer diameters.

[0021] Research conducted by the present inventors has made it possible to develop a method that meets this need while avoiding the problems of existing technology. Summary of the Invention

[0022] To further reduce the dimensions of the microcapsules compared to those obtained by microfluidic emulsification, the inventors have developed a method which includes an additional step to control and reduce the size of the microcapsules.

[0023] In a general aspect, the present invention relates to a method for producing polymeric microcapsules, comprising the steps of: - preparation, using microfluidics, of an emulsion comprising an aqueous continuous phase and a dispersed phase in the form of microdroplets, said dispersed phase comprising a monomer or prepolymer A and a cosolvent that is at least partially miscible in the continuous phase; - partially or completely diffusing the cosolvent of the dispersed phase into the continuous phase by diffusion and / or convection; - carrying out interfacial polymerization by contacting the emulsion microdroplets with a polymerization solution comprising a second monomer B or prepolymer B.

[0024] In a general aspect, the present invention relates to a method for producing polymeric microcapsules, comprising the steps of: - preparation, using microfluidics, of an emulsion comprising an aqueous continuous phase and a dispersed phase in the form of microdroplets, said dispersed phase comprising a monomer or prepolymer A and a cosolvent that is at least partially miscible in the continuous phase; - diffusing the co-solvent of the dispersed phase into the continuous phase by diffusion and / or convection; - carrying out interfacial polymerization by contacting the emulsion microdroplets with a polymerization solution containing a second monomer or prepolymer B.

[0025] The method of the present invention comprises the step of preparing an emulsion in the form of microdroplets from an aqueous continuous phase and a dispersed phase by a microfluidic process, the dispersed phase comprising a monomer A or a prepolymer A, a solvent, and a cosolvent, the cosolvent being at least partially compatible with the continuous phase; - partially or completely diffusing the co-solvent of the dispersed phase into the continuous phase by diffusion and / or convection, which can be carried out in the flow of the emulsion through the microchannel; - carrying out a step of interfacial polymerization by contacting the microdroplets of the emulsion with a polymerization solution comprising a second monomer B or prepolymer B by polycondensation, which step can be carried out continuously or batchwise in a microfluidic device.

[0026] According to another aspect, the present invention relates to a method for producing microcapsules obtainable by the method of the present invention, characterized in that the coefficient of variation is less than 7%.

[0027] According to a general aspect, the present invention relates to a method for producing polymeric microcapsules, comprising the steps of: - preparation, using microfluidics, of an emulsion comprising an aqueous continuous phase and a dispersed phase in the form of microdroplets, said dispersed phase comprising a monomer or prepolymer A and a cosolvent that is at least partially miscible in the continuous phase; - partially or completely diffusing the cosolvent of the dispersed phase into the continuous phase by diffusion and / or convection; - carrying out interfacial polymerization by contacting the emulsion microdroplets with a polymerization solution containing a second monomer or prepolymer B.

[0028] According to one embodiment, the process of the present invention is characterized in that when monomer A or prepolymer A is an acid chloride or an isocyanate, monomer B or prepolymer B is an amine, or when monomer A or prepolymer A is an isocyanate or a carboxylic acid, monomer B or prepolymer B is an alcohol, preferably when monomer A or prepolymer A is an isocyanate and monomer B or prepolymer B is an amine.

[0029] According to one embodiment, the method of the invention is characterized in that the isocyanate is a diisocyanate, preferably chosen from toluene 2,4-diisocyanate (TDI), hexamethylene 1,6-diisocyanate (HDI), isophorone diisocyanate (IPDI), polymeric diphenylmethane diisocyanate (PMDI), hexamethylene diisocyanate biuret (HBD-LV), hexamethylene diisocyanate trimer (HDT-LV (low-viscosity aliphatic polyisocyanate based on hexamethylene diisocyanate trimer)), aliphatic pentamethylene isocyanate diisocyanate (PDI), combinations of these diisocyanates, or preferably hexamethylene diisocyanate biuret (HBD-LV).

[0030] According to one embodiment, the method of the invention is characterized in that the amine is chosen from hexamethylenediamine (HMDA), polyethyleneimine (PEI), ethylenediamine (En), diethylenetriamine (DETA), triethylenetetramine (TETA), arylpolyamines (XDA), aliphatic polyamines (TEPA), polyetheramines, guanidine carbonate, combinations of these amines, preferably En or guanidine carbonate.

[0031] According to one embodiment, the method of the present invention is characterized in that the co-solvent has a solubility in water at 20° C. in the range of 1 g / L to 100 g / L.

[0032] According to one aspect, the process of the invention is characterized in that the co-solvent is chosen from butyl acetate, ethyl acetate, amyl acetate, butyl stearate, preferably butyl acetate or ethyl acetate.

[0033] According to one embodiment, the method of the invention is characterized in that the dispersed phase comprises at least 60% by weight of cosolvent relative to the total weight of the dispersed phase.

[0034] According to one embodiment, the method of the invention is characterized in that said dispersed phase comprises at least one excipient and / or active ingredient and / or solvent.

[0035] According to one embodiment, the method of the invention is characterized in that said dispersed phase contains the following composition relative to the total weight of the dispersed phase: 60% to 90% by weight of a co-solvent: - monomers and / or prepolymers A in a proportion of 3% to 12% by weight; - 7% to 30% by weight of solvent; - Active ingredient and monomer or prepolymer A in a ratio of 3:7.

[0036] According to one embodiment, the process of the invention is characterized in that said continuous phase contains the following composition relative to the total weight of the continuous phase: - 0.1% to 5% by weight of a surfactant, preferably SDS; - Water in moderation.

[0037] According to one embodiment, the method of the invention is characterized in that the spreading step is carried out by passing the emulsion through the microfluidic microchannel.

[0038] According to one embodiment, the method of the invention is characterized in that said polymerization step is carried out continuously in a microfluidic microchannel or batchwise.

[0039] According to another aspect, the present invention relates to a microfluidic device suitable for carrying out any embodiment of the manufacturing method of the present invention.

[0040] According to another aspect, the present invention relates to a microfluidic device suitable for implementing any embodiment of the method of the present invention, the microfluidic device comprising a microchip or a cascade micromixer connected to a microfluidic microchannel (e.g., a microfluidic microchannel having a diameter of 500 μm to 2000 μm).

[0041] According to another aspect, the present invention relates to a microfluidic device suitable for implementing any embodiment of the method of the present invention, the microfluidic device comprising a microchip or a cascade micromixer directly connected to a microfluidic microchannel (e.g., a microfluidic microchannel having a diameter of 500 μm to 2000 μm).

[0042] According to another aspect, the present invention relates to a microfluidic device suitable for implementing any embodiment of the method of the present invention, comprising a microchip or a cascade micromixer directly connected to a microfluidic microchannel made of PTFE and having a diameter between 500 μm and 2000 μm.

[0043] According to another aspect, the present invention relates to a microfluidic device comprising a microchip or cascade micromixer to which microfluidic microchannels made of PTFE and having a diameter of 500 μm to 2000 μm are connected.

[0044] According to another aspect, the present invention relates to a microfluidic device comprising a microchip or cascade micromixer connected to a microfluidic microchannel made of PTFE and having a diameter of 500 μm to 2000 μm.

[0045] According to another aspect, the present invention relates to a microfluidic device comprising a microchip or cascade micromixer directly connected to a microfluidic microchannel made of PTFE and having a diameter of 500 μm to 2000 μm.

[0046] Depending on the nature of the polymer desired, the monomers and / or prepolymers A and B may be selected from:

[0047] [Table 2]

[0048] Without being bound by any particular theory, microdroplets are formed in the process of preparing an emulsion (pre-dispersed droplets) containing a solvent and / or cosolvent, and then, by diffusion and / or convection phenomena, are extracted from the dispersed phase into the continuous phase of the emulsion during flow through the microchannel, resulting in microcapsules with small dimensions, low polydispersity and uniform shell thickness after the process of interfacial polymerization.

[0049] To facilitate diffusion and / or convection phenomena, the co-solvent must be at least partially miscible with water.

[0050] The co-solvent can be selected from compounds having a solubility in water at 20°C in the range of 1 to 100 g / L.

[0051] Examples of cosolvents that are particularly suitable for the present invention include butyl acetate, ethyl acetate, amyl acetate and / or butyl stearate; more particularly suitable are butyl acetate or ethyl acetate.

[0052] The microcapsules produced in this way have uniform dimensions, smaller than the diameter of the pre-diffusion microdroplets (before the cosolvent diffuses into the continuous phase), exhibit low polydispersity (standard deviation of particle size less than 7%), and have a shell with a constant and uniform thickness. [Brief explanation of the drawings]

[0053] [Figure 1](a) Schematic diagram of the device according to the invention. A - reservoir for dispersed phase; B - reservoir for continuous phase; C - pressure pump; D - valve; E - three-way junction; F - microchip; (b) Diagram showing the manufacturing process of the microcapsules according to the invention. [Figure 2] (a) Image of microdroplets during emulsion preparation before cosolvent diffusion (microdroplets before diffusion); (b) Diameter distribution histogram of microdroplets; (c) Image of microdroplets after cosolvent diffusion into the continuous phase (microdroplets after diffusion); (d) Diameter distribution histogram of microdroplets after cosolvent diffusion; (e) Image of microcapsules after interfacial polymerization; (f) Diameter distribution histogram of microcapsules. [Figure 3] Relationship between pre-spreading microdroplet diameter and flow rate - Butyl acetate (BA) BA-60% system. [Figure 4] Images of microdroplet formation in a microchannel: (a) "Drip" regime, where Qc and Qd are 40.0 μL / min and 3.0 μL / min, respectively; (b) "Jet" regime, where Qc and Qd are 110.0 μL / min and 3.0 μL / min, respectively. [Figure 5] Relationship between the diameter of the microdroplets after spreading and the diameter of the microdroplets before spreading - BA-60% system. [Figure 6] Change in diameter of microdroplets with time in different organic phase systems. [Figure 7] Microcapsules observed by scanning electron microscope in the BA-60% system. [Figure 8] Relationship between pre-spreading microdroplet diameter and flow rate in the BA-90% system - BA-90% system. [Figure 9] Images of microdroplet formation in a microchannel. (a) "Drip" regime. Qc and Qd are 60.0 μL / min and 5.0 μL / min, respectively. (b) "Tip flow" regime. Qc and Qd are 100.0 μL / min and 5.0 μL / min, respectively. [Figure 10] Relationship between the diameter of the microdroplets after spreading and the diameter of the microdroplets before spreading - BA-90% system. [Figure 11]Microcapsule-BA-90% system observed under a scanning electron microscope. [Figure 12] Relationship between microdroplet diameter and aqueous phase flow rate - 60% system. [Figure 13] Relationship between microdroplet diameter and aqueous phase flow rate - 90% system. [Figure 14] Image of a microdroplet before spreading. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min. [Figure 15] Size distribution of microdroplets before spreading. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min CV: 40.7% Mean diameter: 19.3 μm. [Figure 16] Size distribution of microdroplets before spreading. Continuous phase flow rate: 60 mL / min - Continuous phase flow rate: 10 mL / min CV: 36.5% Mean diameter: 16.6 μm. [Figure 17] Effect of continuous phase flow rate on the average size of pre-spreading microdroplets. Continuous phase flow rate: 10 mL / min. [Figure 18] Image of a microdroplet after spreading in an ethyl acetate (EA) EA 90% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min. [Figure 19] Size distribution of microdroplets after spreading in EA60% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min - CV: 41.2%. Average diameter: 6.0 μm. [Figure 20] Size distribution of microdroplets after spreading in an EA90% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min. CV: 45.0%. Average diameter: 3.2 μm. [Figure 21] Image of microcapsules in EA 60% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min. [Figure 22] Particle size distribution of microcapsules in EA 60% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min CV: 36.9% Average diameter: 6.3 μm. [Figure 23] Size distribution of microcapsules in 90% EA system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min CV: 33.1% Average diameter: 4.4 μm. [Figure 24] Image of a microdroplet before spreading in an ethyl acetate (EA) EA 90% and 2% SDS system. Continuous phase flow rate: 200 mL / min. Continuous phase flow rate: 200 mL / min. [Figure 25] Image of a microdroplet after spreading in an ethyl acetate (EA) EA 90% and 2% SDS system. Continuous phase flow rate: 200 mL / min. Continuous phase flow rate: 200 mL / min. [Figure 26] Size distribution of microdroplets after spreading in 90% EA and 2% SDS systems. Continuous phase flow rate: 200 mL / min. Continuous phase flow rate: 200 mL / min. DETAILED DESCRIPTION OF THE INVENTION

[0054] Other advantages, features and details of the invention will become apparent from the following detailed description. Each content or embodiment or example described below is a specific example of the invention.

[0055] For the purposes of the present invention, the following definitions apply:

[0056] Emulsion: Two immiscible liquids, one of which forms a dispersed phase in the form of droplets dispersed in a continuous phase.

[0057] The terms "internal phase", "dispersed phase" and "discontinuous phase" are used interchangeably when referring to the dispersed phase.

[0058] The terms "external phase", "dispersion medium phase" and "continuous phase" are used interchangeably when referring to the continuous phase.

[0059] Emulsions in which the dispersed phase is lipophilic (e.g., vegetable oil or mineral oil) and the dispersion medium phase is aqueous (e.g., water) are called O / W emulsions; emulsions in which the dispersed phase is aqueous and the dispersion medium phase is lipophilic are called W / O emulsions (oil-based emulsions).

[0060] Micrometer-sized polymer microcapsules: Capsules having a size of less than 65 μm, preferably 5 to 65 μm, and having a surface covered with a uniform shell.

[0061] Particle: A particle of a solid.

[0062] Microdroplets: Droplets having an average diameter of 80 μm or less, preferably in the range of 0.5 to 80 μm. Microdroplets before and after diffusion correspond to the microdroplets of the present invention before and after diffusion of the solvent from the dispersed phase to the continuous phase.

[0063] Prepolymer: A polymerizable oligomer containing 2 to 5 monomer units.

[0064] Microfluidics: a system for controlling and for the flow of fluids through a network of microchannels, at least one dimension of which is on the order of micrometers.

[0065] The step of preparing an emulsion can be carried out by contacting a solution corresponding to the dispersed phase with a second solution corresponding to the continuous phase in a microfluidic device of the microchip type (preferably a glass-bonded microchip) equipped with a cross-, T-, or Y-type mixer, or a cascade- or lamination-type micromixer, and the microchip is preferably hydrophilic.

[0066] The microfluidic device of the present invention allows the formation of microdroplets of a dispersed phase in a continuous phase. In the microchip, the size of the microdroplets depends on the hydrodynamic regime. Four regimes are distinguished and described below: "dropping," "squeezing," "jetting," or "tip flow." Of these four regimes, the dropping regime is particularly advantageous.

[0067] <Squeezing> At low continuous phase flow rates, large microdroplets block the channel cross section downstream of the junction and eventually detach due to the pressure increase of the upstream continuous phase.

[0068] This flow regime produces large microdroplets, typically around 150 μm in diameter, which is not suitable for the present invention.

[0069] <Drip> Increasing the flow rate of the continuous phase increases the shear stress caused by the continuous phase. The pinching effect of the dispersed phase, due to the absolute stability of the dispersed phase, leads to the formation of microdroplets near the junctions of the microchannels. The microdroplets formed under this flow regime are monodisperse and typically have diameters in the range of 50-100 μm.

[0070] Example of flow rate in this flow regime: For systems with 60% co-solvent (butyl acetate): Dispersed phase: 1μL / min Continuous phase: 40-110 μL / min or Dispersed phase: 3μL / min Continuous phase: 40-90 μL / min or Dispersed phase: 5μL / min Continuous phase: 40-60 μL / min For 90% BA: Dispersed phase: 1μL / min Continuous phase: 40-100 μL / min or Dispersed phase: 3μL / min Continuous phase: 40-100 μL / min or Dispersed phase: 5μL / min Continuous phase: 40-80 μL / min

[0071] <Injection> By increasing the flow rates of the dispersed and / or continuous phases, a jet forms (Figure 4), and convective instabilities squeeze the continuous phase downstream of the junction. When the inertial forces of the dispersed phase and the shear forces of the continuous phase become high enough to overcome interfacial tension (the only force holding the dispersed phase within the junction), the dispersed phase becomes entrained downstream before the instability reaches a critical value required for droplet breakup. The size of the microdroplets in this "jetting" regime is close to that in the "dripping" regime, but with the disadvantage of higher polydispersity than in the "jetting" regime.

[0072] Example flow rates for this flow regime: For systems with 60% co-solvent (butyl acetate): Dispersed phase: 3μL / min Continuous phase: 110 μL / min or more Dispersed phase: 5μL / min Continuous phase: 90 μL / min or more

[0073] <Advanced flow> This is a transitional flow regime between "dropping" and "jetting." In this regime, convection in the continuous phase drives surfactant toward the edge of the dispersed phase, resulting in "superconcentration" of surfactant in that region. The smallest microdroplets, less than 50 μm in diameter, are formed due to interfacial tensions much lower than in the equilibrium state.

[0074] Flow rate in this flow regime: For systems with 90% co-solvent (butyl acetate): Dispersed phase: 5μL / min Continuous phase: 100 μL / min

[0075] A preferred fluid regime is a drop regime, which, depending on the selected flow rate, allows the formation of droplets of defined and controlled size.

[0076] Therefore, by controlling the flow rates of the continuous and dispersed phase solutions, it is possible to form uniformly sized micrometer-sized microdroplets.

[0077] The microdroplets thus obtained have a diameter in micrometers, preferably less than 100 μm, preferably less than 90 μm, more preferably less than 80 μm, even more preferably less than 70 μm, even more preferably less than 60 μm, 50 μm, 40 μm, 30 μm, or even less than 10 μm. The diameter may also be in the range of 0.1 μm to 100 μm, or 15 μm to 50 μm, or 1 μm to 50 μm.

[0078] For example, when using the microfluidic device of the present invention (Figure 1) and setting the flow rate of the continuous phase to 70 μL / min to 80 μL / min and the flow rate of the dispersed phase to 1 μL / min, microdroplets with a diameter of approximately 65 μm can be obtained.

[0079] When the flow rate of the continuous phase is set to 140 μL / min to 150 μL / min and the flow rate of the dispersed phase is set to 1 μL / min, microdroplets with a diameter of about 50 μm can be obtained.

[0080] In a second step, the diameter of these microdroplets is reduced by diffusion and / or convection phenomena during a step of diffusion of the cosolvent (which is at least partially miscible with the continuous phase) contained in the microdroplets into the continuous phase.

[0081] This diffusion of the cosolvent reduces the diameter of the microdroplets.

[0082] This step can be carried out, for example, in a polytetrafluoroethylene microchannel having a diameter of 500 to 2000 μm and a length of more than 30 cm, preferably 30 cm to 1 m, with the emulsion flow rate set to 0.002 m / s to 0.1 m / s.

[0083] Under these conditions, the time for a microdroplet to pass through the microchannel is between 1 and 120 seconds.

[0084] These dispersed microdroplets are then converted into microcapsules during a process of interfacial polymerization by polycondensation by contacting the microdroplets containing a monomer and / or prepolymer A added to the emulsion with a polymerization solution containing a second monomer and / or prepolymer B added to the emulsion.

[0085] The amount of monomer or prepolymer A relative to the total weight of the dispersed phase preferably does not exceed 30% by weight of the total weight of the dispersed phase.

[0086] For example, the dispersed phase can include 12 wt% Prepolymer A (HDB-LV), 28 wt% active ingredient octyl salicylate (OS), and 60 wt% co-solvent (ethyl acetate).

[0087] The molar amount of monomer or prepolymer B in the polymerization solution is adjusted according to the amount of monomer or prepolymer A, and the amount of monomer or prepolymer B is adjusted so as to be in a 5-fold or greater excess over the amount of monomer or prepolymer A.

[0088] Below is an example calculation showing the amount of monomer B and / or prepolymer B (ethylenediamine in this example) of the order of 0.01% by weight relative to the total weight of the polymerization solution:

[0089] Total amount of solution: 1 kg

[0090] Molar mass of ethylenediamine: 60.1 kg / kmol

[0091] Number of moles of ethylenediamine in solution:

[0092]

number

[0093] Number of moles of amino groups (-NH2) in solution: 1.7 x 10 -6 kmol×2=3.4×10 -6 kmol

[0094] Maximum flow rate of dispersed phase in a system with 60% cosolvent (butyl acetate): 5 μL / min

[0095] Collection time: 210 minutes (or 3 hours)

[0096] Density of dispersed phase: 0.937 kg / L

[0097] Mass percentage of HDB-LV in the dispersed phase: 12%

[0098] Mass percentage of isocyanate groups (-NCO) in HDB-LV molecules: 23%

[0099] Molar mass of isocyanate group: 42 kg / kmol

[0100] Number of moles of isocyanate functionality in solution:

[0101]

number

[0102] Ratio of the number of amino groups to the number of isocyanate groups:

[0103]

number

[0104] This example is shown because in this case the amount of monomer B in the solution is at a minimum and the amount of monomer A is at a maximum. In other words, in other chemical compositions the ratio of the number of amine functions to the number of isocyanate functions may be greater than 5.

[0105] For example, the amount of the monomer and / or prepolymer B is in the range of about 0.01% by weight to 1% by weight based on the total weight of the polymerization solution.

[0106] [Table 3]

[0107] The capsules thus produced exhibit the following properties: - The standard deviation of the diameter of the microcapsules is 7% or less and the standard deviation of the diameter of the microdroplets is 2% or less.

[0108] The shell of the microcapsule has a thickness of 700 nm to 1500 nm in capsules with a diameter of 25 μm to 50 μm.

[0109] The diameter of the microcapsules of the present invention is preferably 50 μm to 90 μm, more preferably 10 μm to 50 μm.

[0110] <Dispersed phase> The dispersed phase solution comprises at least one monomer or prepolymer A, a cosolvent, and may comprise additional solvents, excipients, and active ingredients that are soluble in the solvent and / or cosolvent.

[0111] The amount of monomer A or prepolymer A is 30% by weight or less, preferably 3% by weight to 12% by weight, based on the composition of the dispersed phase.

[0112] Cosolvents suitable for the present invention must be at least partially miscible with the aqueous continuous phase. Preferably, the amount of cosolvent is at least 60% by weight, preferably 90% by weight, based on the weight of the dispersed phase.

[0113] Using a cosolvent in an amount greater than 90 wt.% relative to the weight of the dispersed phase, the initial microdroplet diameter can be reduced from 50–80 μm to 24–40 μm, i.e., by approximately 50%, after the solvent has transferred to the continuous phase.

[0114] If an additional solvent is used, this solvent has little or no miscibility with the continuous (aqueous) phase. The amount of solvent in the dispersed phase is 30% or less, or between 7% and 30% by weight of the dispersed phase.

[0115] Additional excipients such as surfactants and active ingredients that are soluble in the solvent can be added to the dispersed phase solution.

[0116] Preferably, the proportion of monomer A or prepolymer A in the dispersed phase is less than 12% by weight, preferably less than 3% by weight, more preferably less than 0.3% by weight.

[0117] The dispersed phase composition of the present invention may include, for example, the following components: 60% to 90% by weight of a cosolvent; 3% to 12% by weight of monomer and / or prepolymer A; 7% to 30% by weight of solvent; Active ingredient and monomer or prepolymer A in a ratio of 3:7.

[0118] Solvents and co-solvents "Solvent" or "co-solvent" refers to a liquid that has the property of dissolving other substances.

[0119] In the process of the present invention, the dispersed phase comprises a co-solvent that is at least partially miscible with the aqueous continuous phase and may further comprise an additional solvent that is immiscible or poorly miscible with the aqueous continuous phase.

[0120] In the present invention, partial miscibility means that the co-solvent has a solubility in water at 20° C. of at least 1 g / L, preferably at least 100 g / L.

[0121] By fully miscible it is meant that 100% of the co-solvent is miscible in water.

[0122] In the present invention, partially miscible means that at least 10% of the co-solvent is miscible in water, or 20% of the co-solvent is miscible in water, or at least 30% of the co-solvent is miscible in water, or at least 40% of the co-solvent is miscible in water, or at least 50% of the co-solvent is miscible in water, or at least 60% of the co-solvent is miscible in water, or at least 70% of the co-solvent is miscible in water, or at least 80% of the co-solvent is miscible in water, or at least 90% of the co-solvent is miscible in water.

[0123] Examples of cosolvents that are particularly suitable for the present invention are selected from dibutyl adipate, n-butyl acetate, ethyl acetate, amyl acetate and butyl stearate.

[0124] The preferred co-solvent is n-butyl acetate.

[0125] Examples of solvents suitable for the present invention include cyclohexane, cycloheptane, cyclohexanone, hexane, heptane, octane, toluene, benzene, xylene, meta- or para-cresol, benzaldehyde, ethyl acetate, ethyl ether, chloromethane, dichloromethane, chloroform, carbon tetrachloride, fluoroform, difluoromethane, alkyl halides, alkene halides, dichloroethane, trichloroethane, tetrachloroethane, trifluoroethane, trichloroethylene, tetrachloroethylene, or mixtures thereof.

[0126] Examples of solvents that are particularly suitable for the present invention are selected from hexadecane, octyl salicylic acid, dibutyl adipate, and dibutyl adipate or Cetiol B.

[0127] The solvent is preferably octyl salicylic acid.

[0128] <Active ingredient> The dispersed phase may include one or more active ingredients such as a phase change material (hexadecane, heptadecane, octadecane, nonadecane, or eicosane), a sunscreen (octyl salicylate or benzyl salicylate), a fragrance (lavender, ethyl salicylate, or limonene), or an insecticide (pirimiphos-methyl or a pyrethroid).

[0129] The active ingredient must be completely dissolved in the solvent and / or cosolvent of the dispersed phase, and its solubility (or miscibility) in the aqueous phase must not exceed 0.1 g / L. Among the active ingredients listed above, esters such as adipic acid have the highest solubility (or miscibility) in the aqueous phase, at approximately 0.1 g / L.

[0130] The amount of active ingredient contained in the dispersed phase ranges from 0% to 28%, e.g., 0% to 28% by weight of the dispersed phase composition, which corresponds to 0% to 70% by weight of the final amount of active ingredient in the microcapsules.

[0131] <Continuous phase> The continuous phase is an aqueous phase comprising water and at least one surfactant, the surfactant preferably comprising 1% or less of the total weight of the continuous phase.

[0132] The surfactants are selected from natural surfactants or synthetic ionic, nonionic, or amphoteric surfactants. Examples of ionic surfactants include sodium lauryl sulfate (SDS). Depending on the phase used, nonionic surfactants are preferably those with a high hydrophilic / lipophilic balance or HLB (e.g., polyoxyethylenated sorbitan derivatives (Tween® type), copolymers of ethylene oxide and propylene oxide (Pluronic® type), or ethers of fatty alcohols and polyoxyethylene glycol), or conversely, surfactants with a low hydrophilic / lipophilic balance (e.g., sorbitan derivatives (Span® type)). Examples of amphoteric surfactants are egg or soy lecithin or its purified derivatives.

[0133] Suitable surfactants for preparing emulsions of the present invention may be selected from, for example, polyvinyl alcohol (PVA), sodium dodecyl sulfonate (SDS), polyoxyethylene sorbitan monooleate (Tween 80), and bio-based surfactants, with SDS being particularly suitable for the present invention.

[0134] <Preparation of emulsion> Emulsions are formed from continuous and dispersed phases brought into contact in a microfluidic device (Dolomite microchip or Ehrfeld micromixer). The size and size distribution of the formed microdroplets (pre-spreading microdroplets) depend on the selected microfluidic device and the operating conditions regarding the flow rates of the continuous and dispersed phases.

[0135] <Cosolvent diffusion> Flow of the emulsion through microchannels (or tubes), typically made of PTFE, allows the cosolvent in the microdroplets to diffuse into the aqueous continuous phase.

[0136] After spreading, the diameter of these microdroplets becomes smaller than the diameter of the original microdroplets. This reduction in diameter of the microdroplets depends on several factors, including the amount of cosolvent used and the kinetics of diffusion and / or convection. Depending on the conditions, the diameter reduction can be as small as 20% or even as large as 50%.

[0137] The flow of emulsion within the microchip is visualized with a camera connected to a built-in Meros High Speed ​​Digital Microscope, as described by Dolomite Microfluidics. Visualization of the emulsion flow through the microchip allows the diameter of the microdroplets to be measured before spreading. The microdroplets exiting the microchannel are collected on a glass slide, and the diameter of the microdroplets after spreading is measured with an optical microscope.

[0138] <Interfacial polymerization> After passing through the microfluidic device, the emulsion passes through microchannels that allow the diffusion of the cosolvent, and is then added to an aqueous solution containing monomer B or prepolymer B. After diffusion, the monomers and / or prepolymers A and B come into contact at the interface of the microdroplets, forming a polymer shell by interfacial polycondensation.

[0139] The interfacial polymerization process can be carried out batchwise, where the emulsion is mixed with the polymerization solution in a suitable reservoir, or it can be carried out continuously in a microfluidic device (Ehrfeld microreactor or tube).

[0140] Depending on the choice of monomers or prepolymers A and B (Table 1), the polymer shell may be a polyamide obtained by polycondensation of diacids or acid chlorides with diamines, a polyurea obtained by polycondensation of diisocyanates with diamines, a polyurethane obtained by polycondensation of diisocyanates with diols, or a polyester obtained by polycondensation of dicarboxylic acids with diols.

[0141] Preferably, the shell is a polyurea obtained using an isocyanate monomer or prepolymer A, where the isocyanate prepolymer can contain 2 to 4 isocyanate groups.

[0142] Isocyanate molecules with low volatility (flash point above 120°C) are preferred due to their low toxicity.

[0143] In one embodiment, the isocyanate is a diisocyanate selected from toluene 2,4-diisocyanate (TDI), hexamethylene 1,6-diisocyanate (HDI), isophorone diisocyanate (IPDI), polymeric diphenylmethane diisocyanate (PMDI), hexamethylene diisocyanate biuret, HDT-LV (a low viscosity aliphatic polyisocyanate based on hexamethylene diisocyanate trimer), aliphatic isocyanates, pentamethylene diisocyanate (PDI).

[0144] In one embodiment, the isocyanate is a prepolymer such as HDB-LV (hexamethylene diisocyanate biuret), HDT-LV, or pentamethylene diisocyanate (PDI), preferably HDB-LV.

[0145] According to another embodiment, the isocyanate is preferably selected from the group consisting of hexamethylene diisocyanate trimer, isophorone diisocyanate trimer or hexamethylene diisocyanate biuret, of which hexamethylene diisocyanate biuret is more preferred, for example HDB-LV.

[0146] Depending on the number of isocyanate groups, the shell of the microcapsule can be crosslinked, thereby increasing the strength of the shell of the microcapsule, decreasing the permeability of the polymer shell, improving the retention of the active ingredient, and adjusting its release profile.

[0147] The monomers and / or prepolymers B used to obtain the polyurea shell are amines, preferably 1,3-diaminopropane, 1,4-diaminobutane, ethylenetriamine, pentaethylenehexamine, hexamethylenediamine, bis(3-aminopropyl)amine, bis(hexamethylene)triamine, tris(2-aminoethyl)amine, triethylenetetramine, N,N'-bis(3-aminopropyl)-1,3-propanediamine, tetraethylenepentamine, pentaethylenehexamine, The amines are selected from branched polyethyleneimine, chitosan, nisin, gelatin, 1,3-diaminoguanidine, 1,1-dimethylbiguanide, guanidine, arginine, lysine, ornithine, hexamethylenediamine (HMDA), polyethyleneimine (PEI), ethylenediamine (DEA), diethylenetriamine (DETA), triethylenetetramine (TETA), arylpolyamines (XDA), aliphatic polyamines (TEPA), polyetheramines, guanidine carbonate, and combinations of these amines.

[0148] Preferably, the polyurea shell is obtained by condensation of a diisocyanate, such as HDB-LV, with a diamine, such as guanidine carbonate or ethylenediamine.

[0149] According to one embodiment of the invention, the polymer shell may be a polyamide obtained by polycondensation of an acid dichloride (monomer or prepolymer A) with an amine (monomer or prepolymer B).

[0150] According to another aspect of the invention, the polymeric shell may be a polyurethane obtained by polycondensation of a diisocyanate with a polyol.

[0151] Examples of polyols include polyvinyl alcohol, butane-1,4-diol, hexane-1,6-diol, propane-1,3-diol, pentane-1,5-diol, octane-1,8-diol, and diols or triols such as ethylene glycol, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, neopentyl glycol, 1,4-butanediol, 1,5-pentanediol, 3-methyl-1,5-hexanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol, 1,12-octadecanediol, 1,4-cyclohexanedimetol, dimer fatty acid diol (dimerisoyldiol), hydroxypivalic acid ester of neopentyl glycol, glycerol, and 1,1,1-trimethylolpropane; 1,2-ethanediol, 1, Low molecular weight dihydric or polyhydric alcohols such as 2-propanediol, neopentyl glycol, dibromoneopentyl glycol, diethylene glycol, triethylene glycol, dipropylene glycol isomers, and tripropylene glycol, butanediol isomers, pentanediol, hexanediol, heptanediol, octanediol, nonanediol, decanediol, undecanediol, 1,3- and 1,4-cyclohexanedimethanol, hydrogenated bisphenol A, fatty alcohol dimers, 1,1,1-trimethylethane, 1,1,1-trimethylolpropane, glycerol, pentaerythritol, sugar alcohols (such as xylitol, sorbitol, mannitol), sugars (such as sucrose), other polyhydric alcohols, low molecular weight alkoxylated products of the above dihydric and polyhydric alcohols, and mixtures of the above alcohols can be used.

[0152] According to another aspect of the present invention, the polymeric shell may be a polyester obtained by polycondensation of a dicarboxylic acid with a polyol. Examples of dicarboxylic acids include sebacic acid, dodecanedioic acid, adipic acid, and methylsuccinic acid. Examples of polyols include 1,9-nonanediol and 1,10-decanediol.

[0153] <Microfluidic Devices> Microfluidic devices allow for the preparation of emulsions.

[0154] The interfacial polymerization process can be carried out in a batch or continuous manner.

[0155] Microfluidic devices suitable for the present invention are cascade or lamination type micromixers (manufactured by Ehrfeld) or microchips (manufactured by Dolomite).

[0156] A micromixer (manufactured by Ehrfeld) is a mixer consisting of multiple channels arranged in parallel or laminated configuration, with a parallel configuration being preferred. It is capable of producing 9 L / h. Scalable devices capable of producing up to 1000 L / h also exist. In one embodiment of the present invention, the flow rate of the dispersed phase solution in the micromixer is 10 mL / min to 100 mL / min, preferably 10 mL / min, and the flow rate of the continuous phase is 20 mL / min to 200 mL / min, preferably 20 mL / min to 200 mL / min, more preferably 20 mL / min, 30 mL / min, 40 mL / min, 50 mL / min, 60 mL / min, 70 mL / min, 80 mL / min, 90 mL / min, 100 mL / min, or 200 mL / min. Flow rates can be generated in the micromixer using two pressure pumps, such as the HNP Mikrosysteme pressure pump, which provides a flow rate of 1 mL / min to 300 mL / min. In the Ehrfeld micromixer, according to the process of the present invention, the equation We=ρ c u 2 The Weber number obtained for the dispersed phase by d / γ is 1-10.

[0157] According to one embodiment, the microchip is made of hydrophilic glass, and the width of the microchannel at the junction with the cross-, T-, or Y-shaped mixer combined with the outlet microchannel is at least 50 μm, or 105 μm. In one embodiment of the present invention, the flow rate of the dispersed phase solution in the microchip is 0.2 μL / min to 7 μL / min, preferably 1 μL / min, and the flow rate of the continuous phase solution is 6 μL / min to 1000 μL / min, preferably 40 μL / min to 150 μL / min, and more preferably 40 μL / min, 60 μL / min, 70 μL / min, 80 μL / min, 90 μL / min, 100 μL / min, 120 μL / min, or 140 μL / min. According to one embodiment, the microfluidic device may include a Dolomite 3D flow-focusing microchip with a 50 μm channel at the junction. Within the microchip, the flow rate can be controlled using two pressure pumps equipped with two flow sensors of the Mitos Flow Rate Sensors type, as described by Dolomite Microfluidics (UK).

[0158] The flow rate of the dispersed phase is 0.2 μL / min to 7 μL / min, and the flow rate of the continuous phase is 6 μL / min to 1000 μL / min. In the microchip, according to the process of the present invention, the flow rate is calculated by the equation We=ρ c u 2 The Weber number obtained for the dispersed phase by d / γ is 10 -4 ~10 -3 It is between.

[0159] The use of microchips is particularly suitable for the production of small, calibrated capsules of less than 50 μm.

[0160] On the other hand, the use of an Ehrfeld micromixer is particularly suitable for the continuous production of capsules with smaller diameters (typically less than 10 μm) and flow rates of about 100 mL / min.

[0161] <Microchannel for cosolvent diffusion> The microchannel or tube in which the diffusion of the cosolvent into the aqueous solution occurs is preferably made of Teflon and has a length of 30 cm to 1 meter. In the microfluidic device, the microchip or micromixer is directly connected at its outlet to the Teflon (PTFE) microchannel.

[0162] The emulsion formed using the reactor is sent to a polytetrafluoroethylene (PTFE) microchannel with a length of 30 cm or more, or 1 meter or more, at a flow rate of 0.1 m / s.

[0163] The diameter of the polytetrafluoroethylene tube or microchannel is between 500 μm and 2000 μm.

[0164] It is important that the microchannel does not have hydrophilic properties that would cause the microdroplets to adhere to its walls and subsequently aggregate.

[0165] [Example 1: Production of microdroplets and microcapsules using Dolomite microchips] This example describes the production of microcapsules consisting of a polyurea shell and a core containing sunscreen, using Dolomite microchips. The experimental results presented demonstrate the feasibility of producing highly monodisperse polyurea microcapsules (coefficient of variation less than 7%) with a minimum size of approximately 20 μm by the method of the present invention.

[0166] Various operating conditions were tested to investigate the effects of: flow rates of the continuous and dispersed phases; Cosolvent usage rate; Selection of co-solvents used.

[0167] In each case, the size of the microdroplets before spreading was compared to the size of the microdroplets after spreading, and the stability of the microdroplets and capsules over time was also analyzed.

[0168] (Experimental device) To prepare water-in-oil (O / W) emulsions, experiments were performed using a hydrophilic borosilicate glass microchip (Droplet Junction Chip, Dolomite Microfluidics, UK). The chip geometry is called a flow-focus type, with a junction width of 105 μm, a collection channel width of 300 μm, and a height of 100 μm.

[0169] The aqueous and organic phases are delivered using two pressure pumps (Mitos P-Pump, response time <4 s, Dolomite Microfluidics, UK). These pumps are equipped with two sensors: a Mitos flow sensor with a response time of 0.2–7 μL / min for the dispersed phase and a Mitos flow sensor with a response time of 6–1000 μL / min for the continuous phase (Mitos flow sensor with a response time <30 ms, Dolomite Microfluidics, UK). The droplet formation and flow regimes are visualized using a high-speed camera with a built-in microscope (Meros High-Speed ​​Digital Microscope, 4000 fps, Dolomite Microfluidics, UK). The experimental setup for microfluidic emulsification is shown in Figure 1(a).

[0170] Organic pre-diffusion microdroplets are first formed and then flow into a 30 cm Teflon microchannel, where the cosolvent is extracted from the microdroplets by diffusion and / or convection, thereby reducing the size of these microdroplets (step 2 in Figure 1(b)).

[0171] In the final step (step 3 in Figure 1(b)), interfacial polymerization continues for 4 days at room temperature (25°C).

[0172] (Chemistry) The dispersed phase contains a cosolvent, a polyisocyanate prepolymer, HDB-LV, and an active ingredient, octyl salicylate (OS); the aqueous phase contains water and sodium dodecyl sulfate (SDS).

[0173] In this example, the percentage of free isocyanate groups in the hexamethylene diisocyanate biuret (HDB-LV, Vencorex Chemicals) molecule is 23.5 ± 1.0 wt% based on the total weight of the organic phase. Sodium dodecylsulfonate (Across Organics, pure grade), ethylenediamine (Sigma Aldrich, >99%), octyl salicylate (Sigma Aldrich, >99%), butyl acetate (Sigma Aldrich, ACS reagent, >99%), and ethyl acetate (ACS reagent, >99%) were used without further purification. Distilled water was prepared using a pot still (GFL 2008). All liquids were previously filtered through a syringe filter (JVLAB, PTFE, 0.45 μm pore size).

[0174] Ethyl acetate and butyl acetate were used as co-solvents.

[0175] The continuous phase is composed of 1 wt % SDS and 99 wt % water based on the total weight of the aqueous phase.

[0176] The aqueous solution in the beaker contains 0.01% by weight of ethylenediamine and 1% by weight of SDS based on the total weight of the aqueous phase.

[0177] (Experimental Method) For each operating condition, the experiment is repeated at least three times to ensure reproducibility.

[0178] To investigate the effect of the continuous phase flow rate, the solvent concentration in the dispersed phase, and the solubility of the solvent in water on the formation of polyurea microcapsules, various chemical systems were tested, and the results are summarized in Table 4. For each chemical system, four different sizes of microcapsules were produced using different continuous phase flow rates.

[0179] The process comprises the following steps: - Prepare the solution of the continuous phase; - preparing the solution of the dispersed phase; - contacting the dispersed phase with the continuous phase in a microchip connected to a PTFE microchannel; - Flowing the emulsion through a PTFE (or Teflon) microchannel so that the cosolvent in the dispersed phase can diffuse into the continuous phase; After spreading the emulsion, the microdroplets are brought into contact with the polymerization solution, and the microcapsules thus formed can be collected with a pipette, air-dried on a glass slide, and subjected to analysis.

[0180] Preparation of the continuous phase: - While measuring the weight on a balance, add 1% SDS by mass to a beaker and adjust with water. - Add a magnetic stirrer and stir for 30 minutes while heating to below 50°C. - Filtration of aqueous phase: Aspirate the solution into a syringe. Attach a syringe filter and rinse the flask with the filtrate. Aspirate the solution into a syringe and transfer the filtered solution into a clean flask.

[0181] Preparation of the dispersed phase: - 60% system: Add 60% by mass of the co-solvent (butyl acetate or ethyl acetate depending on the experiment), 12% HDB-LV, and 28% OS to a vial while weighing on a balance. - 90% system: Add 90% by mass of the co-solvent (butyl acetate or ethyl acetate depending on the experiment), 3% HDB-LV, and 7% OS to a vial while weighing on a balance. - Add a magnetic stirrer, seal the vial securely with the stopper and stir for 30 minutes. - Filtration of the organic phase: Aspirate the solution into a syringe. Attach a syringe filter and rinse the flask with the filtrate. Aspirate the solution into a syringe and transfer the filtered solution into a clean flask.

[0182] Two co-solvents were tested: butyl acetate and ethyl acetate. Table 4 summarizes the co-solvents used and the designation of the experiments based on their composition.

[0183] [Table 4]

[0184] BA: butyl acetate EA: Ethyl acetate

[0185] Preparation of emulsion: - Place the aqueous phase flask in the reservoir at the inlet of the pump for the continuous phase; - Place the organic phase flask in the reservoir at the inlet of the dispersed phase pump; - Start the pump; - Set the flow rate of the dispersed phase (Qd) to 1 μL / min to 5 μL / min; - Set the continuous phase flow rate (Qc) between 40 μL / min and 150 μL / min;

[0186] Interfacial polymerization: - Prepare a beaker containing 1 kg of aqueous phase of 0.01% ethylenediamine (aqueous phase polymerization solution); - After spreading, the microdroplets are collected in a beaker at the outlet of the microchannel where the cosolvent diffusion occurs and placed in the aqueous phase polymerization solution; - Microcapsules are formed in a beaker in the presence of ethylenediamine.

[0187] The interfacial polymerization is continued at room temperature for 4 days.

[0188] The molar amount of amino groups in the beaker is at least five times greater than the molar amount of isocyanate functions in the collected microdroplets.

[0189] Characterization of microdroplets and microcapsules The size of the microdroplets and microcapsules before and after spreading is measured. To evaluate the shell thickness, a droplet of the microcapsule suspension is deposited on a glass slide and cut with a cover glass using an optical microscope. The slide with the broken microcapsules is then attached to an SEM support. Finally, the microcapsules attached to the SEM support are air-dried for 12 hours. To measure the average shell (skin) thickness, at least three different capsules are cut and measured.

[0190] The pre-spreading microdroplet formation and flow regime are visualized using a high-speed camera with a built-in microscope (Meros High Speed ​​Digital Microscope, Dolomite Microfluidics Ltd. ©, UK).

[0191] Samples of the microdroplets and microcapsules were taken after the cosolvent diffusion step and after polymerization, respectively, after which the samples were observed under an optical microscope. The droplets were collected on an optical microscope plate and analyzed.

[0192] Microdroplets and microcapsules with diameters between 10 µm and 100 µm were analyzed by image analysis, either manually or using image processing software. Images acquired with the microscope were recorded in the AM Scope software with a scale of 1 real µm corresponding to 3.782 pixels or 1 real µm corresponding to 0.946 pixels, depending on the selected resolution.

[0193] (result) Monodispersity of pre-spreading microdroplets, post-spreading microdroplets, and microcapsules The coefficient of variation (CV) of diameter was calculated based on photographs of the microdroplets before and after spreading, and the microcapsules. The diameter size distribution obtained using the BA-60% system is shown in Figure 2. The flow rates of the continuous phase (Qc) and dispersed phase (Qd) were 85.0 μL / min and 1.0 μL / min, respectively.

[0194] The average CV values ​​calculated for the microdroplets before and after spreading, and the capsules are 0.63%, 0.97%, and 6.27%, respectively. By using the microfluidic device, the microdroplets exhibit high monodispersity with CV values ​​of approximately 1% both before and after spreading.

[0195] Tables 5, 6 and 7 show the reproducibility of the results based on experiments performed in triplicate.

[0196] [Table 5]

[0197] [Table 6]

[0198] [Table 7]

[0199] Effect of continuous and dispersed phase flow rates and cosolvent ratios The co-solvent used was butyl acetate (BA). The results of experiments carried out at different flow rates of each phase and co-solvent ratios are shown below.

[0200] BA60% results Figure 3 shows the variation of droplet size with the flow rates of the continuous and dispersed phases in a system containing 60% butyl acetate. These experiments required the use of two different flow rate regimes, dripping (a) and spraying (b), as shown in Figure 4.

[0201] At a constant organic phase flow rate, increasing the aqueous phase flow rate results in smaller microdroplet sizes.

[0202] The relationship between the size of the microdroplets before and after spreading is shown in Figure 5. The results are reproducible.

[0203] Regardless of the flow rate used, the average factor α (ratio of the diameter of the microdroplets before spreading to the diameter of the microdroplets after spreading) can be estimated to be 1.37, which is quite close to the theoretical value of 1.41, with a relative difference of 2.8%.

[0204] This theoretical factor (α) can be calculated as follows:

[0205]

number

[0206] In the above formula, d pre is the size of the microdroplet before spreading, and d post is the theoretical size of the microdroplet after spreading, and ρ orga is the density of the organic phase, and ρ HDB / OS is the density of the mixture of HDB-LV and octyl salicylic acid at a mass ratio of 3 / 7, and w HDB / OS is the mass percentage of HDB-LV and octyl salicylic acid in the organic phase.

[0207] Figure 6 shows the time course of the diameter of the dispersed microdroplets. Five minutes after collection, most of the cosolvent had dispersed. Additional experiments showed that all of the cosolvent had dispersed after two minutes.

[0208] Figure 7 shows the shape of the obtained microcapsules. The morphology is clearly spherical. There are no noticeable pores on the surface. The skin is airtight and may have an irregular outer surface. Table 8 shows the skin thickness measured in three identical experiments.

[0209] [Table 8]

[0210] BA90% results Figure 8 shows the variation of microdroplet size with respect to the flow rates of the continuous and dispersed phases. These experiments required the use of two different flow rate regimes: dripping and tip flow, as shown in Figure 9.

[0211] At a constant organic phase flow rate, increasing the aqueous phase flow rate results in smaller microdroplet sizes.

[0212] The microdroplet formation conditions in Figure 9(b) are an aqueous phase flow rate of 100 μL / min and an organic phase flow rate of 5 μL / min, which are considered to be very advantageous conditions because they allow the formation of very small, monodisperse microdroplets at high flow rates.

[0213] FIG. 10 shows the relationship between the size of the microdroplets after spreading and the size of the microdroplets before spreading.

[0214] Regardless of the flow rate used, the average factor α (ratio of the diameter of the microdroplets before spreading to the diameter of the microdroplets after spreading) can be estimated to be 2.10, which is close to the theoretical value of 2.27, with a relative difference of 7.5%.

[0215] Figure 11 shows the morphology of the obtained microcapsules. They are spherical. The skin is airtight and has an irregular outer surface. Table 9 shows the thickness of the skin measured in three identical experiments.

[0216] [Table 9]

[0217] Effect of cosolvent choice Ethyl acetate (EA) was used as the second co-solvent. For reference, Table 10 shows the physicochemical properties of the two co-solvents.

[0218] [Table 10]

[0219] Results for EA60% system The change in droplet size versus continuous phase flow rate using a system containing 60% ethyl acetate is shown in Figure 12. In these experiments, a dropwise regime was used.

[0220] When the flow rate of the organic phase is kept constant (1 μL / min), the size of the microdroplets decreases as the flow rate of the aqueous phase increases.

[0221] Regardless of the flow rate used, the average factor α (ratio of the diameter of the microdroplets before spreading to the diameter of the microdroplets after spreading) can be estimated to be 1.36, which is quite close to the theoretical value of 1.40, with a relative difference of 2.8%.

[0222] EA90% results The variation of microdroplet size with the flow rate of the continuous and dispersed phases is shown in Figure 13. In these experiments, the dripping regime was used.

[0223] When the flow rate of the organic phase is kept constant (1 μL / min), the size of the microdroplets decreases as the flow rate of the aqueous phase increases.

[0224] Regardless of the flow rate and fluid regime used, the average factor α (ratio of pre-diffusion microdroplet diameter to post-diffusion microdroplet diameter) can be estimated to be 2.15, which is close to the theoretical value of 2.26, with a relative difference of 5.6%.

[0225] Two cosolvents are suitable for reducing the size of microcapsules and can achieve similar results.

[0226] (Conclusion) The dispersion (coefficient of variation (CV)) of the droplets is particularly narrow, with CVs ranging from 0.3% to 0.6%. For microcapsules, they have the same size as the microdroplets after spreading. The CV for microcapsules is approximately 6% to 7%.

[0227] Tests confirmed that the size of the microdroplets decreases from when they are formed in the microchip until they exit the microchannel due to the diffusion of the co-solvent. After the diffusion of the co-solvent in the PTFE microchannel, the size of the pre-diffusion microdroplets decreases by 20% to 50%.

[0228] The various values ​​of the factor α obtained for the operating conditions are summarized in Table 11.

[0229] [Table 11]

[0230] The two solvent systems tested showed similar results, confirming that the performance of the invention is independent of the co-solvent selected.

[0231] The skin thickness of the microcapsules ranges from 0.6 to 1.4 mm depending on the size of the microcapsules.

[0232] [Example 2: Production of microdroplets and microcapsules using an Ehrfeld cascade micromixer]

[0233] This example describes the production of microcapsules consisting of a polyurea shell and a core containing a solvent (Cetiole B) using an Ehrfeld micromixer. The experimental results presented demonstrate the feasibility of producing polyurea microcapsules with a minimum size of a few micrometers using the method of the present invention.

[0234] Various operating conditions were tested to investigate the effects of: flow rates of the continuous and dispersed phases; Cosolvent usage rate.

[0235] (Experimental device) The cascade micromixer used is a static micromixer that combines two fluids by repeated, offsetting splits in the transverse direction, leading to the confluence of the two fluids, according to the "split and recombine" principle [Ehrfeld Cascade Mixer Operating Manual, OI-0216-3, 2012]. Thus, with each recombination, the number of fluid layers present doubles and their diameter is halved.

[0236] By repeating this procedure 11 times, a large number of fluid layers with diverse compositions can be generated, which is a method for achieving rapid material transport within a mixture.When two immiscible liquids are introduced into a micromixer at a relatively high flow rate, the high shear forces within the mixing channel create an emulsion.

[0237] This type of mixer can also be used for very viscous liquids or liquids containing particles. Furthermore, the particularly low pressure drop allows high flow rates even for highly viscous liquids. The modules used can also be temperature controlled by heat transfer mechanisms above and below the mixing structure.

[0238] The preferred temperature is 25°C, but can be varied to adjust the viscosity.

[0239] The cascade micromixer has two inlet channels and one outlet channel combined with a 53.5 cm long polytetrafluoroethylene (PTFE) microchannel. The microfluidic flow phase flow volume is L = 53.5 cm, d internal =2mm.

[0240] Therefore, the volume of this microchannel is V = 4.24 × 10 -5 mL.

[0241] At a flow rate of 100 mL / min, the transit time is 1.01 seconds.

[0242] Two pumps are used to feed the dispersed and continuous phases into the micromixer.

[0243] The organic pre-diffusion microdroplets then flow into a Teflon tube or microchannel where the co-solvent is extracted from the microdroplets by diffusion and / or convection, thereby reducing the size of these microdroplets.

[0244] At the outlet of the microchannel, the emulsion is transferred to a beaker filled with the polymerization solution, where the interfacial polymerization reaction proceeds at room temperature for 4 days.

[0245] (Chemistry) The dispersed phase contains a cosolvent, a polyisocyanate prepolymer, HDB-LV, and a solvent; the aqueous phase contains water and sodium dodecyl sulfonic acid (SDS).

[0246] In this example, the percentage of free isocyanate groups in the hexamethylene diisocyanate biuret (HDB-LV, Vencorex Chemicals) molecule is 23.5 ± 1.0 wt% relative to the total weight of the organic phase. Ethylenediamine (Sigma Aldrich, >99%), octyl salicylate (Sigma Aldrich, >99%), ethyl acetate (ACS reagent, >99%), and Cetiol B are used without further purification. Distilled water is prepared using a pot still 2008 (GFL). All liquids are filtered beforehand through a syringe filter (JVLAB, PTFE, 0.45 μm pore size).

[0247] Ethyl acetate is used as a co-solvent and Cetiol B acts as a solvent.

[0248] The continuous phase is composed of 1 wt % SDS and 99 wt % water based on the total weight of the aqueous phase.

[0249] The aqueous solution in the beaker contains 0.01% by weight of ethylenediamine and 1% by weight of SDS based on the total weight of the aqueous phase.

[0250] (Experimental Method) The experimental method was the same as that described in Example 1, except that octyl salicylic acid was replaced with Cetiol B.

[0251] Table 12 summarizes the co-solvents used and the designation of the experiments based on their composition.

[0252] [Table 12]

[0253] (result) Monodispersity of microdroplets before spreading Figure 14 shows photographs of the microdroplets before spreading at given dispersed and continuous phase flow rates. It is clear that the microdroplet sizes are polydisperse, as shown in the microdroplet diameter distributions in Figures 15 and 16. In the two flow rate ranges presented, the CVs are 36.5% and 40.7%, respectively.

[0254] The main advantage of this mixer is not the size control of the microdroplets, but the ability to use much higher flow rates than would be permitted by a microchip. The flow rates of the two phases can be operated at 200 mL / min each, whereas in a microchip the flow rate of the dispersed phase is measured in μL / min, and is therefore 200,000 times smaller. Ehrfeld also sells a scalable device that allows flow rates approaching 1,000 L / h.

[0255] Effect of flow rates of continuous and dispersed phases Figure 17 shows the effect of the continuous phase flow rate on the size of the pre-spreading microdroplets. As the flow rate increases, the size of the microdroplets decreases. For example, when the flow rate increases from 50 mL / min to 60 mL / min, the average diameters become 19.3 μm and 16.6 μm, respectively. A similar effect is observed when increasing the flow rate of the dispersed phase. An increase in either of the two flow rates decreases the size of the pre-spreading microdroplets.

[0256] Effect of cosolvent ratio The co-solvent used was ethyl acetate. The experimental results for varying the co-solvent ratio at fixed flow rates of the continuous and dispersed phases are shown below. Figure 18 shows that the average particle size of the microdroplets after spreading is much smaller than that of the microdroplets before spreading, and this phenomenon becomes more pronounced as the co-solvent ratio increases. Table 13 below summarizes the results shown in Figures 19 and 20.

[0257] [Table 13]

[0258] In terms of the coefficient of variation (CV), the microdroplets after spreading are as polydisperse as the microdroplets before spreading. In the 60% EA and 90% EA systems, the ratio α is 3.2 and 6.0, respectively, indicating that a size reduction was obtained. The difference between the experimental and theoretical values ​​undoubtedly arises from the polydispersity of the obtained sizes.

[0259] Microcapsule characteristics A photograph of the microcapsules obtained with the EA 60% system is shown in Figure 21. Figures 22 and 23 show the diameter distribution of capsules formed using the EA 60% and EA 90% systems. The values ​​are summarized in Table 14.

[0260] [Table 14]

[0261] It can be noted that the properties of the capsules are very similar to those of the microdroplets after spreading, both in terms of mean diameter and coefficient of variation.

[0262] (Conclusion) Tests confirmed that the size of the microdroplets decreases from when they are formed in the micromixer until they exit the microchannel due to the diffusion of the cosolvent. After the diffusion of the cosolvent in the PTFE microchannel, the size of the pre-diffusion microdroplets decreases by up to a factor of 6.

[0263] The microdroplets and microcapsules before and after spreading have polydisperse sizes.

[0264] The concept of the present invention has been verified in an Ehrfeld cascade mixer, which allows for much higher production flow rates than possible using microchips, and is also capable of achieving capsule sizes approaching the micrometer range.

[0265] [Table 15]

[0266] [Table 16-1]

[0267] [Example 3: Production of microdroplets and microcapsules with a diameter of 1 μm using a cascade micromixer manufactured by Ehrfeld] This example describes the production of microcapsules consisting of a polyurea shell and a core containing sunscreen using an Ehrfeld micromixer. The experimental results presented demonstrate the feasibility of producing polyurea microcapsules with a diameter of 1 μm using the inventive method. The effect of varying the surfactant concentration was investigated.

[0268] (Experimental device) The cascade micromixer used is a static micromixer that combines two fluids by repeated, offsetting splits in the transverse direction, leading to the confluence of the two fluids, according to the "split and recombine" principle [Ehrfeld Cascade Mixer Operating Manual, OI-0216-3, 2012]. Thus, with each recombination, the number of fluid layers present doubles and their diameter is halved.

[0269] By repeating this procedure 11 times, a large number of fluid layers with diverse compositions can be generated, which is a method for achieving rapid material transport within a mixture.When two immiscible liquids are introduced into a micromixer at a relatively high flow rate, the high shear forces within the mixing channel create an emulsion.

[0270] This type of mixer can also be used for very viscous liquids or liquids containing particles. Furthermore, the particularly low pressure drop allows high flow rates even for highly viscous liquids. The modules used can also be temperature controlled by heat transfer mechanisms above and below the mixing structure.

[0271] The preferred temperature is 25°C, but can be varied to adjust the viscosity.

[0272] The cascade micromixer has two inlet channels and one outlet channel combined with a 53.5 cm long polytetrafluoroethylene (PTFE) microchannel. The microfluidic flow phase flow volume is L = 53.5 cm, d internal =2mm.

[0273] Therefore, the volume of this microchannel is V = 4.24 × 10 -5 mL.

[0274] At a flow rate of 200 ml / min, the transit time is 0.50 seconds.

[0275] Two pumps are used to feed the dispersed and continuous phases into the micromixer.

[0276] The organic pre-diffusion microdroplets then flow into a Teflon tube or microchannel where the co-solvent is extracted from the microdroplets by diffusion and / or convection, thereby reducing the size of these microdroplets.

[0277] At the outlet of the microchannel, the emulsion is transferred to a beaker filled with the polymerization solution, where the interfacial polymerization reaction proceeds at room temperature for 4 days.

[0278] (Chemistry) The dispersed phase contains a cosolvent, a polyisocyanate prepolymer HDB-LV, and a solvent. The aqueous phase contains water and sodium dodecyl sulfonic acid (SDS).

[0279] In this example, the percentage of free isocyanate groups in the hexamethylene diisocyanate biuret (HDB-LV, Vencorex Chemicals) molecule is 23.5 ± 1.0 wt% based on the total weight of the organic phase. Ethylenediamine (Sigma Aldrich, >99%), octyl salicylic acid (Sigma Aldrich, >99%), and ethyl acetate (ACS reagent, >99%) are used without further purification. Distilled water is prepared using a pot still 2008 (GFL). All liquids are filtered beforehand through a syringe filter (JVLAB, PTFE, 0.45 μm pore size).

[0280] The dispersed phase contains the co-solvent ethyl acetate, the polyisocyanate prepolymer HDB-LV, and the active ingredient octyl salicylate (OS).

[0281] The continuous phase is composed of 1-2 wt % SDS and 99-98 wt % water based on the total weight of the continuous phase.

[0282] The aqueous solution in the beaker contains 0.01% by weight of ethylenediamine and 1% by weight of SDS based on the total weight of the aqueous phase.

[0283] (Experimental Method) The experimental method is the same as that described in Example 2, except that Cetiol B is replaced with octyl salicylic acid. The optimal flow rates of the dispersed and continuous phases are set at 200 ml / min, respectively.

[0284] Table 16 summarizes the co-solvents used and the designation of the experiments based on their composition.

[0285] [Table 16-2]

[0286] [Table 17]

[0287] (result) Effects of the active ingredient Table 18 summarizes the information on the size of the microdroplets after diffusion in an aqueous phase containing 1% SDS. The droplet size in this example, with a CV of 27.5%, clearly demonstrates a lower polydispersity than the droplets produced in Example 2, with a CV of 45.0%. The average size of the final droplets reaches 3.5 μm, which, with other parameters being identical, is comparable to the value in Example 2 (3.2 μm). Therefore, the use of octyl salicylic acid as the active ingredient, rather than cetiol B, makes it possible to generate highly monodisperse droplets after diffusion in ethyl acetate.

[0288] [Table 18]

[0289] Effect of surfactant concentration The experimental results are shown below, where the SDS concentration in the aqueous phase was set to 2% and the flow rates of the continuous and dispersed phases were fixed at 200 ml / min. Figures 24 and 25 show that the average size of the droplets before and after spreading is much smaller than the size of the droplets produced under conditions containing 1% SDS in the aqueous phase. This is because the interfacial tension between the oil and aqueous phases decreases as the surfactant concentration increases. Table 19 below summarizes the results shown in Figures 24 and 25.

[0290] [Table 19]

[0291] Regarding the CV (Figure 26), the microdroplets before and after spreading are more monodisperse than those prepared with a solution containing 1% SDS in the aqueous phase. The largest number of microdroplets has a diameter between 0.8 and 1.2 μm. The experimental and theoretical α ratios are 3.18 and 2.26, respectively, and these values ​​are quite close. The difference between the experimental and theoretical values ​​undoubtedly arises from the polydispersity of the obtained sizes. These values ​​are lower than those obtained in Example 2, when Cetiol B was used as the active ingredient.

[0292] (Conclusion) Tests confirmed that the size of the microdroplets decreased from when they were formed in the micromixer until they left the microchannel due to the diffusion of the cosolvent. After the diffusion of the cosolvent in the PTFE microchannel, the size of the pre-diffusion microdroplets decreased by a factor of up to 3.18, which is very close to the theoretical value of 2.26.

[0293] The microdroplets before and after spreading show a more monodisperse size distribution when octyl salicylic acid is used instead of cetiol B as the active ingredient.

[0294] The concept of the present invention has been verified in an Ehrfeld cascade mixer, which allows for much higher production flow rates than possible using microchips, and is also capable of achieving capsule sizes approaching the micrometer range.

[0295] [Table 20]

[0296] [Table 21]

Claims

1. A method for producing polymeric microcapsules comprising the steps of: a. Using microfluidic technology, preparing an emulsion comprising an aqueous continuous phase and a dispersed phase in the form of microdroplets, the dispersed phase comprising a monomer or prepolymer A and a cosolvent that is at least partially miscible in the continuous phase; b. Allowing the co-solvent of the dispersed phase to partially or completely diffuse into the continuous phase by diffusion and / or convection; c) contacting the emulsion microdroplets with a polymerization solution containing a second monomer or prepolymer B, thereby carrying out interfacial polymerization.

2. When the monomer A or the prepolymer A is an acid chloride or an isocyanate, the monomer B or the prepolymer B is an amine, or when the monomer A or the prepolymer A is an isocyanate or a carboxylic acid, the monomer B or the prepolymer B is an alcohol, preferably, the monomer A or the prepolymer A is an isocyanate and the monomer B or the prepolymer B is an amine; The method of claim 1.

3. the isocyanate is a diisocyanate, preferably selected from toluene 2,4-diisocyanate (TDI), hexamethylene 1,6-diisocyanate (HDI), isophorone diisocyanate (IPDI), polymeric diphenylmethane diisocyanate (PMDI), hexamethylene diisocyanate biuret (HBD-LV), hexamethylene diisocyanate trimer (HDT-LV (low viscosity aliphatic polyisocyanate based on hexamethylene diisocyanate trimer)), aliphatic pentamethylene isocyanate diisocyanate (PDI), a combination of these diisocyanates, preferably hexamethylene diisocyanate biuret (HBD-LV); The method according to claim 1 or 2.

4. amines selected from hexamethylenediamine (HMDA), polyethyleneimine (PEI), ethylenediamine (En), diethylenetriamine (DETA), triethylenetetramine (TETA), arylpolyamines (XDA), aliphatic polyamines (TEPA), polyetheramines, guanidine carbonate, and combinations of these amines, preferably En or guanidine carbonate; The method according to any one of claims 1 to 3.

5. The co-solvent has a solubility in water at 20°C within the range of 1 g / L to 100 g / L. The method according to any one of claims 1 to 4.

6. the co-solvent is selected from butyl acetate, ethyl acetate, amyl acetate, butyl stearate, preferably butyl acetate or ethyl acetate; The method according to any one of claims 1 to 5.

7. The dispersed phase contains 60% by weight or more of the co-solvent based on the total weight of the dispersed phase. The method according to any one of claims 1 to 6.

8. characterized in that the dispersed phase comprises at least one excipient and / or active ingredient and / or solvent, The method according to any one of claims 1 to 7.

9. The dispersed phase is characterized in that it contains, relative to the total weight of the dispersed phase, the following composition: a. 60% to 90% by weight of a co-solvent; b. Monomer and / or prepolymer A in a ratio of 3% to 12% by weight; 7% to 30% by weight of solvent; c. Active ingredient and monomer or prepolymer A in a ratio of 3:7 The method according to any one of claims 1 to 8.

10. The continuous phase is characterized in that it contains the following composition relative to the total weight of the continuous phase: a. 0.1% to 5% by weight of a surfactant, preferably SDS; b. Appropriate amount of water The method according to any one of claims 1 to 9.

11. The spreading step is carried out by passing the emulsion through a microfluidic microchannel. The method according to any one of claims 1 to 10.

12. The polymerization step is carried out continuously or batchwise in a microfluidic microchannel; The method according to any one of claims 1 to 11.

13. A microfluidic device comprising a microchip or cascade micromixer connected to microfluidic microchannels made of PTFE and having a diameter of 500 μm to 2000 μm.

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